2. Academic Validation
  3. Triphenylphosphonium conjugation to a TRAP1 inhibitor, 2-amino-6-chloro-7,9-dihydro-8H-purin-8-one increases antiproliferative activity

Triphenylphosphonium conjugation to a TRAP1 inhibitor, 2-amino-6-chloro-7,9-dihydro-8H-purin-8-one increases antiproliferative activity

  • Bioorg Chem. 2022 Sep;126:105856. doi: 10.1016/j.bioorg.2022.105856.
Sujae Yang 1,  Nam Gu Yoon 2,  Min-A Park 2,  Jisu Yun 1,  Jin Young Im 2,  Byoung Heon Kang 3,  Soosung Kang 4
Affiliations

Affiliations

  • 1 College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
  • 2 Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
  • 3 Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919, Republic of Korea. Electronic address: kangbh@unist.ac.kr.
  • 4 College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea. Electronic address: sskang@ewha.ac.kr.
PMID: 35661618 DOI: 10.1016/j.bioorg.2022.105856
Abstract

Tumor-necrosis-factor-receptor associated protein 1 (TRAP1), a mitochondrial paralog of heat shock protein 90 family proteins, is overexpressed in many Cancer cells and supports tumorigenesis by rewiring vital metabolic and cell death pathways. The triphenylphosphonium moiety is used to deliver therapeutic cargo to increase drug uptake into mitochondria. Various aryl- or alkyl-substituted phosphonium analogs were conjugated with TRAP1-selective inhibitors 4a-c to optimize Anticancer activity. Among these various phosphonium-conjugated compounds, (6-(2-amino-9-(4-bromo-2-fluorobenzyl)-6-chloro-8-oxo-8,9-dihydro-7H-purin-7-yl)hexyl)triphenylphosphornium (6a) was identified as a potential Anticancer agent. Compound 6a had IC50 values of 0.30-3.24 μM in seven different Cancer cell lines and potently suppressed tumor growth without any noticeable in vivo toxicity in a nude mouse model xenografted with PC3 prostate Cancer cells.

Keywords

Hsp90; Inhibitor; Mitochondria; TRAP1; Triphenylphosphonium.

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